PROJECT SUMMARY The importance of coronary atherosclerosis and its clinical manifestations cannot be overstated; in this country, half a million people die from acute myocardial infarction every year and an equal number of patients survive with substantial morbidity. Coronary atherosclerosis is an inflammatory process governed by dysregulated endothelium, leukocytes, macrophages, and smooth muscle cells. These cells conspire to form lesions within the artery wall, effectuate plaque progression or regression, and play a critical role in precipitating thrombosis, which can block blood flow to the heart. Progress towards improving the understanding, diagnosis, and treatment of coronary artery disease has been slowed by our inability to observe these cells in the coronary arteries of living human patients. Our laboratory has been on the forefront of pushing the resolution limits of coronary imaging in vivo. In the parent R01, we developed an intracoronary imaging technology, optical frequency domain imaging (OFDI), that makes it practical to obtain 10-m resolution, three-dimensional images of the coronary wall in the clinical setting. Now that OFDI has been transferred to the commercial sector, we will focus our efforts on developing the next generation coronary imaging technology, one that will provide images at a resolution of 1-m. This advance will enable the investigation of macromolecules and cells involved in the pathophysiology of CAD and will allow clinicians to diagnose and treat this disease based on cellular information obtained from their patients' coronary arteries. The research strategy of this project parallels that of our previous development and translation of intracoronary OFDI. First, new OCT technology will be designed and fabricated, focusing on solving catheter and system- level challenges. Alongside this development process, we will validate the accuracy of OCT ex vivo for identifying relevant cellular and subcellular features of the coronary wall, using histopathology as a gold standard. The safety, feasibility, and efficacy of OCT will then be evaluated in 25 patients undergoing coronary intervention. !